Cleaning and disinfection of GMP areas

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Important points to be considered when implementing a new disinfection programme are facility design, documentation, selection of agents, and the process of fumigation

Ayo Ogunsanlu
MSc, C Biol

Peter Cowin
BSc, MRSC
Quality Assurance Unit
Imperial College Healthcare NHS Trust
Pharmacy Department
Charing Cross Hospital
London, UK

The compounding of patient doses is typically carried out in pharmaceutical clean rooms that are designed and built to comply with specifications laid down in the European Union legislation publication The rules governing medicinal products in the European Union (Eudralex).[1] Volume 4 of Eudralex specifies the guidelines for good manufacturing practices (GMP) for medicinal products for human and veterinary use, and contains specific guidelines for the preparation and manufacture of sterile medicinal products and the microbiological specifications that clean rooms have to meet. There is an array of engineering solutions to help achieve these goals. Of particular importance are: facility design; contained (closed system) processing; and the air handling systems. However, despite all engineering solutions implemented, people are the main source of microbiological contamination in clean rooms. The fact that people have to utilise these facilities for the preparation of medicinal products means there will always be a microbiological challenge to the GMP areas. A well- planned cleaning and disinfection programme is therefore essential for any unit to comply with EU GMP cleanliness requirements.
This article reviews the important points to be considered when implementing a new cleaning and disinfection programme and discusses issues around facility design, documentation, selection of disinfectant/cleaning agents, and the process of fumigation, which is increasingly used in the hospital pharmacy environment.

Facility design
The ease of cleaning of the premises should be considered at the design stage. Details that need to be considered are:

• Smooth, impervious, stain resistant surfaces for floors, walls and ceilings.

• The colours of the floors should be selected such that dust and dose forms will be clearly visible on the surface. For example, in a tablet facility, the range of tablets should be placed on a sample of the flooring to test that the colour/pattern of the floor does not camouflage any of the medications.

• Coving at floor-to-wall and ceiling-to-wall joints.

• No ledges or crevices where dust could settle.

• Minimal non-essential equipment in the production areas, eg, desks and cupboards.

Documentation
Sufficiently detailed cleaning methods should be documented in standard operating procedures to allow for consistency of operation between different cleaning operators. For example, stating that a piece of equipment should be ‘taken to the cleaning area and cleaned with alcohol wipes’ is insufficient detail.
Cleaning procedures should be in place before the commencement of any cleaning validation programme. Where necessary, procedures should distinguish between the requirements for cleaning:

• Between batches of the same product and strength, ie, within a campaign.

• Between product campaigns of the same product.

• Between different products or strengths.

• After scheduled or unscheduled stoppages, eg, planned maintenance, calibration or spillages.

Procedures are required for the cleaning of floors, walls and ceilings (and any other items such as computers, printers and process equipment present in the area, eg, isolators, laminar air flow cabinets, biological safety cabinets, etc). Procedures should include:

• Details of the equipment or areas to be cleaned.

• Frequency of cleaning, ie, daily, weekly, etc.

• The responsibilities for the cleaning operations.

• In larger facilities, location of the cleaning operation (eg, in the process area or wash bay).

• The sequence of steps for cleaning.

• The cleaning agents to be used and their concentration.

• The type of cloths used for washing or drying (eg, disposable, non-fibre shedding cloths)

• A statement specifying that an inspection of the equipment should be made to ensure that it is visually clean, dry and clear of any residues from the cleaning agents.

• A statement specifying the requirement for the completion of records.

• How equipment should be cleaned and how dried equipment should be labelled and stored.

• Status labelling of areas, this is especially applicable in large facilities and where the cleaning takes place in the absence of production staff.

Cleaning agents/disinfectants
There are clear but minimal guidelines in Eudralex about cleaning agents. The guideline states that ‘cleaning agents used for the cleaning of Grades A and B areas should be sterile before use and that prepared disinfectants should be kept in previously cleaned containers and stored for periods specified in local procedures’.[1] There is also a requirement to monitor cleaning agents for microbiological contamination.

Rotation of disinfectants
There is one guideline, however, which has caused a great deal of debate among cleanroom operators and that is the practice of rotation of disinfectants. It is stated that, ‘where disinfectants are used, more than one type should be employed. Monitoring should be undertaken regularly in order to detect the development of resistant strains’.[1] While the advantages of rotation or the employment of more than one type of cleaning agent is widely recognised and accepted by cleanroom operators, there are frequent discussions among microbiologists and quality assurance personnel about the perceived benefits of disinfectant rotation on minimising the development of resistant strains. The advantages of a good well-thought out rotation system are, among others:

• Based on a focus on the range of microbial isolates picked up in the production facility, rotation enables the Unit to respond accordingly with appropriate products. Rotation of disinfectants often follows the path of one non-oxidising product, eg, phenol or quaternary ammonium compound, followed by a sporicide, eg, chlorine dioxide or hydrogen peroxide.

• A single non-oxidiser will often not have the spectrum of activity needed to eradicate all microbial species encountered in the facility. Moulds, for example, may be more difficult to control than vegetative bacteria, so it is good practice to have another option (sporicidal or not) that has a different mode of action or activity.

• Having a rotational programme makes options available if one of the chosen disinfectants leaves more residue than another (favour the one that leaves least residue, use the other less frequently).

• Rotation also allows mitigation against corrosion and other material compatibility issues (use the least corrosive one more often).

• One disinfectant may have better surfactant properties over another (eg, it cleans and disinfects) so offers options if process residue is an issue.

• Rotation provides options for possible Health and Safety reasons or other non specific problems eg, operator preference (pungent smell for example).

• Cost.

Most crucially, while there is mention of rotation, or the use of more than one disinfectant, there are no stated instructions on frequency of rotation and having more than one validated cleaning agent or disinfectant allows exploitation of the above advantages.

Is development of resistance a real or perceived problem?
In an interesting article, Murtough et al[2] argue that a major reason for this confusion is because users compare antibiotic efficacy with that of disinfectants. In support of rotation, they argue that resistance to biocides can develop (and they provide evidence to support that idea) and also that in some cases organisms are intrinsically resistant to certain types of compounds, so rotating prevents the selection of these organisms which gives the impression of resistance. The evidence provided against the principle of rotation asserts that the majority of biocides (unlike antibiotics) have a gross effect on the bacterial cell with multiple sites of action, while most antibiotics have very specific modes of action, also in clean rooms, there is unlikely to be a significant number of organisms present for the required interaction between cells to aid spontaneous mutation or plasmid transfers. They conclude that, ‘there is no definite in-use evidence to support the value of biocide rotation’. That conclusion is supported in another article.[3] Martinez distinguishes between common disinfectants (agents that lack specificity in their microbiocidal action) and ‘antibiotic-like’ disinfectants (agents which like antibiotics have specialised cell targets) and concludes that, ‘rotation of a common disinfectant and a sporicidal helps ensure that bacterial spores do not take hold in manufacturing and aseptic areas. But the rotation of common disinfectants, such as those based on phenol-derivatives (except Triclosan), aldehydes, and oxidizing agents, has no scientific basis. If antibiotic-like disinfectants are used, however, rotation is a necessity’.
Typically, most hospital establishments have eliminated the rotation of a disinfectant to a disinfectant and have replaced such practice with the routine use of a broad spectrum disinfectant complemented by the routine use of a sporicide on a less frequent basis than the disinfectant. That rotation strategy exceeds the potential efficacy performance of a disinfectant to another disinfectant. A typical disinfectant provides a broad spectrum of kill over a larger array of vegetative cells at higher populations (106 organisms at normally 10 min). A cold steriliant/sporicide provides the guarantee of the absence of any microorganisms even at very high levels, but its efficacy is very dependent upon very long contact times ie, typically >10 min. At lower levels (below 103 organisms) it is effective in short contact times of 5 min.

[[HPE52.45]]
Justification for the use of cleaning agents/disinfectants
In several cases, the selection of cleaning agents and disinfectants is based on historical grounds, which have then become accepted practice; such scenarios should be challenged. The unjustified use of cleaning agents and disinfectants is not good practice because it introduces a potential contaminant to the products made in the Unit. The major justification for the use of a cleaning or disinfecting agent is the inability to clean without the cleaning agent.
The use of cleaning agents and disinfectants directly on product contact surfaces should be avoided or at least minimised wherever possible. However, there may be occasions where a cleaning agent or disinfectant is required for a process (such as in the cleaning of greasy equipment). When the need for a cleaning agent or disinfectant has been identified, a number of steps have to be considered prior to selection and use. These are:

• The cleaning agent or disinfectant has to be validated and where possible, tested against commonly isolated organisms prior to its use.

• The cleaning efficiency has to be considered, this is linked to the type of agent selected (eg, non-ionic, cationic, anionic). Non-foaming agents are preferred because they are removed easily.

• Compatibility with equipment and absorption on to surfaces, eg, seals, should be considered.

• For cleaning agents, non-toxic agents are preferable for product contact areas.

• If they are to be used in rotation, compatibility between agents also needs to be considered.

In general terms, the best cleaning agents/disinfectants for use are those with the simplest composition (eg, absence of colours and perfumes) and those for which the suppliers are prepared to provide comprehensive in-house validation and product characteristic details.

Types of disinfectants
There are a myriad of disinfectants available and several of these are manufactured with cleaning properties to eliminate the need to carry out a cleaning stage before the application of the disinfectant. The most commonly used are shown in Table 1.
The most common combination of disinfectants is the use of amphoteric surfactants in rotation with quaternary ammonium compounds. Chlorine-based disinfectants and hydrogen peroxide are strong oxidisers and sporicidal and are typically reserved for use on a less frequent basis, most commonly after planned preventative maintenance or equipment servicing work has been carried out in the GMP areas.

Fumigation
Another disinfection (decontamination) method increasing in popularity is fumigation. Traditionally, formaldehyde was used for the fumigation process but because of health and safety concerns, has now been replaced by other gases, such as vaporised hydrogen peroxide (VHP). VHP is the most commonly used gas for fumigation because:

• It produces a high spectrum of kill activity at low temperatures.

• It breaks down into oxygen and water and eliminates the issues with residues on surfaces and product contact parts.

There are a number of units available on the market, but typically, the sterilisation cycle is performed in four stages:

• Dehumidification: reduction of relative humidity of the enclosure or room to be fumigated.

• Conditioning: stage at which the hydrogen peroxide vapour is brought to the required concentration.

• Biodecontamination: once the desired concentration is achieved, the hydrogen peroxide vapour concentration is maintained for the specified duration to achieve decontamination, and

• Aeration: the stage where the hydrogen peroxide vapour is eliminated from the enclosure or room.

Cycle times vary with initial temperature and humidity; enclosure type, size and configuration; and load. The process is typically fully automated and most systems will monitor and record vital cycle parameters.

Conclusions
The hospital pharmacist is presented with a variety of choices when it comes to the selection of agents for cleaning and disinfection of GMP areas. Effective cleaning programmes are achieved after integration into the design of the facility, after consideration of the processes carried out in the facility and incorporation into the regular staff training schedule. The involvement of the local microbiologist is important in the identification of the most commonly isolated microbial contaminants and the subsequent selection of active disinfectants.

References
1. European Commission. The rules governing medicinal products in the European Union (Eudralex). Volume 4. EU guidelines to good manufacturing practice, medicinal products for human and veterinary use. Annex I, manufacture of sterile medicinal products (November 2008).
2. Murtough SM et al. J Hosp Infect 2001;48(1):1–6.
3. Martinez J. Pharm Tech 2009;33(2):58–71.